This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A major challenge for public health officials is predicting the outbreak of diseases. Zoonotic diseases are a particular challenge since little is known about the specific mechanisms behind host switching. For example, what abiotic factors increase the probability of host switching? The proposed research is an interdisciplinary investigation that will provide insight into the mechanisms behind viral host switching. Our central hypothesis, which is based on preliminary results from our current research, is that viral adaptation to small increases in temperature enhances capsid stability, which in turn increases the likelihood of viral host switching. We are interested in differences in temperature of a few degrees, such as the difference between mammalian and avian body temperature, or the change that might occur in parts of the world due to global warming. This is a highly interdisciplinary study that brings together a computational biophysicist, an evolutionary biologist and a statistician for a multipronged attack on a hypothesis that could have major implications for human health. We will test our central hypothesis via the following specific aims: (i) Use experimental evolution to test the hypothesis that viruses carrying adaptive mutations for increased temperature are more likely to switch hosts than the wild type viruses. (ii) Use biophysical modeling to test the hypothesis that some mutations involved in viral host switching increase the stability of the capsid. (iii) Use statistical and spatial modeling to explore the probability of host switching and the dynamics of spread in a spatially heterogeneous environment.